This information is intended for use by health professionals

1. Name of the medicinal product

Anagrelide AOP 0.5 mg hard capsules

2. Qualitative and quantitative composition

Each capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide.

Excipient with known effect

Each capsule contains 94 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Hard capsule.

Blue hard capsule in size 4 with dimensions 14.3±0.3 mm filled with a white powder.

4. Clinical particulars
4.1 Therapeutic indications

Anagrelide AOP is indicated for the reduction of elevated platelet counts and associated clinical symptoms in at high risk essential thrombocythemia patients.

An at high risk essential thrombocythaemia patient is defined by one or more of the following features:

- Age ≥ 60 years

- Platelet count ≥ 1.000 x 109/l

- Increase of platelet count ≥ 300 x 109/l within 3 months

- Severe thrombohaemorrhagic or ischaemic symptoms in anamnesis

- Vascular risk factors

4.2 Posology and method of administration

Posology

Treatment with Anagrelide AOP should be initiated by physicians experienced in the treatment of patients with essential thrombocythaemia.

The dosage of Anagrelide AOP has to be determined individually for each patient and needs to be controlled by the physician.

The recommended starting dose of Anagrelide AOP is 0.5 to 1.0 mg per day. The starting dose should be maintained for at least one week. After one week, the dose can be adjusted individually to obtain the lowest dose necessary to keep the platelet count <600 x 109/l. The ideal platelet count lies between 150 x 109/l and 400 x 109/l.

An increase of the daily dose should not exceed 0.5 mg per week and the maximum single dose should not exceed 2.5 mg. A dosage of more than 5 mg per day should not be administered.

If the total daily dose is higher than 0.5 mg per day, Anagrelide AOP should be administered BID (every 12 hours) or TID (every 8 hours).

The effect of treatment with Anagrelide AOP should be controlled regularly (see section 4.4).

Upon treatment initiation, the platelet count should be measured weekly until the individual optimal response is reached (normalisation of platelet count or a reduction to <600 x 109/l). Afterwards the platelet count should be controlled in regular intervals according to the physicians´ discretion.

Normally, a decrease of the platelet count can be seen within 14 to 21 days after treatment initiation. In most patients an adequate therapeutic response can be reached and maintained with a dose between 1 and 3 mg per day.

Anagrelide AOP is intended for continuous use. Upon discontinuation of Anagrelide AOP, platelet counts will increase within 4 to 8 days and within 10 to 14 days, pre-therapy values are reached.

Elderly

Age-specific dose changes were not necessary for the treatment of elderly patients with anagrelide.

Renal impairment

There are no specific pharmacokinetic data available for this patient population. Therefore the potential risks and benefits of anagrelide therapy in patients with renal insufficiency should be assessed before treatment is commenced (see sections 4.3, 4.4 and 5.1). Treatment with anagrelide in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) is contraindicated (see section 4.3).

Hepatic impairment

There are no specific pharmacokinetic data available for this patient population. Hepatic metabolism represents the most important path for drug clearance and liver function and may therefore be expected to influence this process. Potential risks and advantages of a therapy with anagrelide have to be considered prior to a treatment in patients with mild hepatic impairment (see sections 4.3 and 4.4).

Treatment with anagrelide in patients with moderate or severe hepatic insufficiency is contraindicated (see section 4.3).

Paediatric population

The safety and efficacy of anagrelide in children aged up to 18 years has not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

For oral use. Anagrelide AOP capsules must be swallowed whole with a small amount of liquid.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Cardiovascular disease grade 3 with a negative benefit/risk assessment or grade 4 (South West Oncology Group criteria)

- Severe renal insufficiency (creatinine clearance < 30 ml/min)

- Moderate to severe hepatic insufficiency

4.4 Special warnings and precautions for use

General

Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks.

The therapy requires close clinical supervision of the patient including a complete blood count (haemoglobin, white blood cell and platelet counts) and tests regarding liver function (e.g. ALT and AST), renal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium).

Cardiovascular effects

Serious cardiovascular adverse events, including cases of torsade de pointes, ventricular tachycardia, cardiomyopathy, cardiomegaly and congestive heart failure have been reported (see section 4.8).

Caution should be taken when using anagrelide in patients with known risk factors for prolongation of the QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong the QTc interval and hypokalaemia.

Close monitoring for an effect on the QTc interval is advisable.

Care should also be taken in populations that may have a higher maximum plasma concentration (Cmax) of anagrelide or its active metabolite, 3-hydroxy-anagrelide, e.g. in case of hepatic impairment or use with CYP1A2 inhibitors (see section 4.5).

A pre-treatment cardiovascular examination, including a baseline ECG and an echocardiography is recommended prior to initiating therapy with anagrelide. Patients should be monitored during treatment for evidence of cardiovascular effects that may require further cardiovascular examination and investigation. Hypokalaemia or hypomagnesaemia must be corrected prior to anagrelide administration and should be monitored periodically during therapy.

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III) and because of its positive inotropic and chronotropic effects, anagrelide should be used with caution in patients of any age with known or suspected heart disease. Moreover, serious cardiovascular adverse events have also occurred in patients without suspected heart disease and with normal pre-treatment cardiovascular examination.

Palpitations and headaches were often observed mainly at the beginning of the therapy (see section 4.8).

These undesired effects can be reduced by a slow increase of the dosage with a starting dose of 0.5 to 1.0 mg per day and normally abate within few weeks.

Pulmonary hypertension

Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy.

Hepatic impairment (see sections 4.2 and 4.3)

In patients with hepatic impairment, frequent liver function tests, especially at the beginning of the therapy, are necessary.

Renal impairment (see sections 4.2 and 4.3)

In patients with renal impairment, frequent kidney function tests especially at the beginning of the therapy are necessary.

Anagrelide AOP contains lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted.

The following drugs were used simultaneously with anagrelide: acetylsalicylic acid, acetaminophen, β-blockers, ACE-inhibitors, clopidogrel, coumarine, folic acid, amlodipine, carbamazepine, hydrochlorothiazide, indapamide, furosemide, iron, isosorbide mononitrate, levothyroxin-Na, simvastatin, ticlopidine, ranitidine, hydroxyurea, allopurinol and digoxin.

With the exception of acetylsalicylic acid (elevated risk of bleeding) no significant interactions could be observed.

Effects of other substances on anagrelide:

• Anagrelide is primarily metabolised by CYP1A2. CYP1A2 is inhibited by several medicinal products, including fluvoxamine, enoxacin and omeprazole, and such medicinal products could theoretically adversely influence the clearance of anagrelide.

In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide.

• Caution should be taken when using anagrelide in patients with medicinal products that can prolong the QTc interval and hypokalaemia.

Effects of anagrelide on other substances:

• Anagrelide demonstrates a somewhat limited inhibitory activity towards CYP1A2, which may present a potential for interaction with other co-administered medicinal products sharing this clearance mechanism e.g. theophylline.

• Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties such as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.

• An in vitro study in human whole blood demonstrated that the anti-aggregatory effects of acetylsalicylic acid were additively, but not synergistically increased by the presence of anagrelide.

At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide may theoretically potentiate the effects of other medicinal products that inhibit or modify platelet function, e.g. acetylsalicylic acid.

Co-administration of repeat-dose anagrelide and acetylsalicylic acid may enhance the anti-platelet aggregation effects of each drug compared with administration of acetylsalicylic acid alone. In some ET patients concomitantly treated with acetylsalicylic acid and anagrelide formulations, major haemorrhages occurred. Therefore, due to the lack of data in ET patients, the potential risks of the simultaneous use of anagrelide with acetylsalicylic acid should be assessed before treatment is initiated, particularly in patients with a high risk profile for haemorrhage.

• Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of hormonal oral contraceptives.

Food interactions

Food delays the absorption of anagrelide but does not significantly alter systemic exposure. The effects of food on bioavailability are not considered clinically relevant to the use of anagrelide.

It has been demonstrated that grapefruit juice inhibits CYP1A2 and thus may reduce the clearance of anagrelide.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of anagrelide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown and therefore, anagrelide is not recommended during pregnancy. If anagrelide is used during pregnancy, or if the patient becomes pregnant while using the medicinal product, she should be advised of the potential risk to the foetus.

Women of child-bearing potential

Women of child-bearing potential should use adequate birth control measures during treatment with anagrelide.

Breast-feeding

It is unknown whether anagrelide/metabolites transfer to human milk. Available data in animals have shown excretion of anagrelide/metabolites in milk. A risk to the newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment with anagrelide.

Fertility

No human data on the effect of anagrelide on fertility are available. In male rats, there was no effect on fertility or reproductive performance with anagrelide. In female rats, using doses in excess of the therapeutic range, anagrelide disrupted implantation (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and operate machinery have been performed. In clinical development, dizziness was a commonly reported side effect.

Patients are advised not to drive or operate machinery while taking Anagrelide AOP if dizziness is experienced.

4.8 Undesirable effects

The most frequent side effects of anagrelide, which were mostly slight in intensity and decreased during the course of the therapy, were: headaches, palpitations, oedemas, nausea and diarrhoea.

These side effects are to be expected due to the pharmacologic effect of anagrelide (inhibition of phosphodiesterase III; see section 5.1). By slowly increasing of the dosage with a starting dose of 0.5 to 1.0 mg per day these effects can be reduced.

The following undesirable effects are ranked according to system organ class and to their frequency:

Very common (≥ 1/10)

Common (≥1/100 to < 1/10)

Uncommon (≥1/1.000 to < 1/100)

Rare (≥ 1/10.000 to < 1/1.000)

Very rare (< 1/10.000)

Not known (cannot be estimated from the available data)

Blood and the lymphatic system disorders

Common:

anaemia, ecchymosis

Uncommon:

thrombocytopenia, bleeding, haematoma

Metabolism and nutrition disorders

Common:

oedema

Uncommon:

weight gain

Nervous system disorders

Very common:

headaches

Common:

vertigo, paraesthesia, insomnia

Uncommon:

depression, nervousness, xerostomia, migraine

Eye disorders

Uncommon:

vision anomalies, conjunctivitis

Ear and labyrinth disorders

Uncommon:

tinnitus

Cardiac disorders

Common:

palpitations, tachycardia, hypertension

Uncommon:

cardiac insufficiency, congestive heart failure, arrhythmia, supraventricular tachycardia, ventricular tachycardia, syncope

Rare:

atrial fibrillation, angina pectoris, myocardial infarction, orthostatic hypotension

Not known:

Torsade de pointes

Respiratory, thoracic and mediastinal disorders

Common:

epistaxis

Uncommon:

pulmonary hypertension, dyspnoea, respiratory infection

Rare:

pleura effusion, pneumonia, asthma

Not known:

pulmonary fibrosis

Gastrointestinal disorders

Common:

nausea, diarrhoea, dyspepsia

Uncommon:

vomiting, flatulence, obstipation, abdominal pain

Rare:

gastritis, loss of appetite

Skin and subcutaneous tissue disorders

Common:

eczema

Uncommon:

alopecia, pruritus

Rare:

skin rash

Musculoskeletal, connective tissue and bone disorders

Common:

backaches

Uncommon:

myalgia, arthralgia

Renal and urinary disorders

Uncommon:

renal insufficiency, infection of the urinary tract

Rare:

nycturia

Not known:

tubulointerstitial nephritis

Hepatobiliary disorders

Rare:

liver enzyme values increased

General disorders and administration site conditions

Common:

fatigue

Uncommon:

pain, weakness

Rare:

influenza like symptoms, ague, malaise

The following undesirable effects of anagrelide are reported in literature:

Pancytopenia, fluid retention, loss of weight, confusion, amnesia, somnolence, loss of coordination, dysarthria, diplopia, cardiomegaly, cardiomyopathy, pericardial effusion, vasodilatation, pleural effusion, pulmonary hypertension, pulmonary infiltrates, allergic alveolitis, anorexia, pancreatitis, gastrointestinal haemorrhage, gastrointestinal disorder, colitis, gingival bleeding, dry skin, increased serum-creatinin values, chest pain, fever, asthenia, impotence

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

At higher than recommended dosages anagrelide produces a reduction in blood pressure, which may cause hypotension as well as tachycardia. A single dose of 5 mg anagrelide can reduce blood pressure usually accompanied by vertigo.

There have been a small number of reports of overdose with anagrelide. Reported symptoms include sinus tachycardia and vomiting. Symptoms improved with conservative management.

A specific antidote for anagrelide has not been identified.

In case of overdose close clinical observation of the patient is necessary. This includes monitoring of the platelet count with regard to thrombocytopenia. If required the dose should be decreased or administration discontinued until the platelet count returns to the normal range.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic substances, ATC code: L01XX35

Mechanism of action

Anagrelide causes a dose dependent and selective decrease in platelet count in humans; the specific mechanism of action is not yet fully understood.

Anagrelide is an inhibitor of cyclic AMP PDE III.

In vitro studies on megakaryocytopoesis in humans have demonstrated that the inhibiting effect on platelet production is caused by a delay in maturation and a reduction of size and ploidy of megakaryocytes. Biopsies of bone marrow of treated patients gave evidence for similar in vivo effects.

Pharmacodynamic effects

Effects on Heart Rate and QTc Interval

The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study in healthy adult men and women.

A dose related increase in heart rate was observed during the first 12 hours, with the maximum increase occurring around the time of maximum concentrations. The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.

A transient increase in mean QTc was observed for both doses during periods of increasing heart rate and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg.

At therapeutic doses, anagrelide does not cause significant changes in white blood cells and coagulation parameters, but may cause minor changes in red blood cells.

At high, non-therapeutic doses anagrelide inhibits c-AMP phosphodiesterasis and ADP- and collagen induced thrombocyte aggregation.

5.2 Pharmacokinetic properties

Absorption

Approximately 75% of anagrelide is absorbed by the gastrointestinal tract of humans after oral administration. In healthy volunteers the time to maximal plasma level (Tmax) was approximately 1.38 hours, the elimination half-life was also approximately 1.38 hours.

A study of the pharmacokinetics revealed a delayed Tmax as well as a reduced Cmax and AUC of Anagrelide AOP compared with another anagrelide containing drug. This delayed invasion of the active substance of Anagrelide AOP - despite the same activity - may be the reason for the different profile regarding side effects.

The absorption of anagrelide by the gastrointestinal tract is delayed by simultaneous ingestion. The culmination of the maximum plasma level can be delayed by up to 2 hours. This fact has no significant effect on bioavailability and clinical activity.

Distribution

Anagrelide has a high volume of distribution (12 l/kg). The distribution into different compartments as well as the degree of plasma protein binding is unknown.

Metabolism

Anagrelide is intensively metabolised, mainly by CYP1A2 in the liver to form 3-hydroxyanagrelide which is further metabolized to 2-amino-5,6-dichloro-3,4,-dihydroquinazoline. 3-hydroxyanagrelide like anagrelide, affects megakaryopoesis and exhibits an even stronger effect with regard to phosphodiesterase III inhibition.

Elimination

After administration of C14 labelled anagrelide, 75% of radioactivity is excreted within 6 days via urine, 10 % via faeces.

Accumulation of anagrelide should not occur as part of a long-term administration because of the short half-life. This assumption is supported by clinical data: upon stopping treatment platelet counts recover to pre-therapy levels within 4 to 8 days.

Elderly

Pharmacokinetic data of patients with myeloproliferative disease treated with anagrelide for 4 weeks were analysed. Plasma levels were comparable in patients < 65 years (n= 16) and ≥ 65 years (n=18).

Paediatric population

Pharmacokinetic data from fasting children and adolescents (age range 7 - 16 years) with essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelide were higher in children/adolescents as compared to adults. There was also a trend to higher exposure to the active metabolite.

5.3 Preclinical safety data

Repeated dose toxicity

Following repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focal myocardial necrosis was observed at 1 mg/kg/day (12 to 16-fold the maximum therapeutic dose) or higher in males and females with males being more sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to 0.1, 0.1, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426 and RL603, respectively.

Reproductive toxicity

Fertility

In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1000 times a 2 mg/day dose, based on body surface area) was found to have no effect on fertility and reproductive performance. In female rats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos was observed at 30 mg/kg/day. The NOEL (10 mg/kg/day) to this effect was 143, 12 and 11-fold higher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites BCH24426 and RL603, respectively.

Embryofoetal development studies

Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo resorption and foetal mortality.

In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg produced a non-adverse increase in gestational duration. At the NOEL dose (3 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 14, 2 and 2-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day.

Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus respectively. At the NOEL dose (30 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day, respectively.

Mutagenic and carcinogenic potential

Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects.

In a two-year rat carcinogenicity study, non-neoplastic findings were observed and related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal phaeochromocytomas was increased relative to the control group in males at all dose levels (≥3 mg/kg/day) and in females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to 37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas of epigenetic origin could be related to an enzyme induction of the CYP1 family. They were observed in females receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1 mg twice daily dose.

6. Pharmaceutical particulars
6.1 List of excipients

Capsule contents

Lactose monohydrate, povidone K30, crospovidone type A, microcrystalline cellulose (E460), magnesium stearate (E470b)

Capsule shell

Titanium dioxide E171, indigo carmine E 132, gelatine, water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

Discard this medicine 100 days after first opening.

6.4 Special precautions for storage

Do not store above 30°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with child-resistant tamper-evident polypropylene cap with a desiccant insert. Pack size of 100 hard capsules.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

AOP Orphan Pharmaceuticals AG

Wilhelminenstraße 91/II f

1160 Vienna

Austria

8. Marketing authorisation number(s)

PL 21344/0023

9. Date of first authorisation/renewal of the authorisation

19/11/2018

10. Date of revision of the text

19/11/2018